Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA

Simons, F. Estelle R.; Shikishima, Yasufumi; Nest, Gary Van; Eiden, Joseph; HayGlass, Kent T.

doi:10.1016/j.jaci.2004.03.003

Cited by 191 publications

(115 citation statements)

References 34 publications

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“…23). This finding is further supported by recent clinical trials in which Amb a1 linked to CpG-DNA improved symptom relief and immunomodulation of the allergic response in patients with allergic rhinitis (24,25).…”

supporting

confidence: 58%

Protective CD8 T Cell Immunity Triggered by CpG-Protein Conjugates Competes with the Efficacy of Live Vaccines

Heit

Schmitz

O’Keeffe

et al. 2005

The Journal of Immunology

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In contrast to infectious (live) vaccines are those based on subunit Ag that are notoriously poor in eliciting protective CD8 T cell responses, presumably because subunit Ags become insufficiently cross-presented by dendritic cells (DCs) and because the latter need to be activated to acquire competence for cross-priming. In this study, we show that CpG-Ag complexes overcome these limitations. OVA covalently linked to CpG-DNA (CpG-OVA complex), once it is efficiently internalized by DCs via DNA receptor-mediated endocytosis, is translocated to lysosomal-associated membrane protein 1 (LAMP-1)-positive endosomal-lysosomal compartments recently shown to display competence for cross-presentation. In parallel, CpG-OVA complex loaded DCs become activated and acquire characteristics of professional APCs. In vivo, a single s.c. dose of CpG-OVA complex (10 μg of protein) induces primary and secondary clonal expansion/contraction of Ag-specific CD8 T cells similar in kinetics to live vaccines; examples including Listeria monocytogenes genetically engineered to produce OVA (LM-OVA) and two viral vector-based OVA vaccines analyzed. Interestingly, CpG-OVA complex induced almost equal percentages of Ag-specific memory CD8 T cells as did infection with LM-OVA. A single dose vaccination with CpG-OVA complex protected mice against lethal doses of LM-OVA. These data underscore that the synergy imparted by CpG-OVA complex-mediated combined triggering of innate and specific immunity might be key to initiate CD8 T cell-based immunoprotection by synthetic vaccines based on subunit Ag.

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supporting

confidence: 58%

Protective CD8 T Cell Immunity Triggered by CpG-Protein Conjugates Competes with the Efficacy of Live Vaccines

Heit

Schmitz

O’Keeffe

et al. 2005

The Journal of Immunology

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“…10 The administration of the Amb a 1-oligodeoxynucleotide conjugate in atopic patients was associated with significant improvements in nasal symptoms, downregulation of IgE, a transient increase in specific IgG levels, and locally reduced numbers of eosinophils and IL-4-producing cells. [11][12][13] Regarding TLR7/8 agonists, 3M012, which belongs to the imidazoquinoline family, conjugated to the HIV Gag protein after UV exposure enhanced the magnitude of the immune response in the mouse. 14 By using the same conjugation procedure, it was also observed that vaccination with an ovalbumin/3M042-coupled compound resulted in an IL-12p40-and type I interferondependent strong CD4 1 and CD8 1 T H 1 immunity, promoting antigen uptake by several resident and migratory DC subsets.…”

mentioning

confidence: 99%

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Filì¹,

Vultaggio²,

Cardilicchia³

et al. 2013

Journal of Allergy and Clinical Immunology

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Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of T H -related transcription factors. Lung cells and sera of nDer p 2-Conjsensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2-Conj stimulated IL-12 and IFN-a production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T H 2-related cytokines and increased IFN-g levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-g upregulation together with IgE downregulation, and an increase in allergenspecific IgG 2a levels in sera. The conjugate exhibited reduced ability to activate human FcεRI 1 cells without inducing T H 17 cells or autoantibodies.

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“…The Amb a 1-ISS combination was more effective in modulating the cytokine profile than the use of ISS and Amb a 1 unlinked [44]. A subsequent in vivo study demonstrated that ragweed-induced TH2 responses were shifted toward TH1 responses, with significant increases in IFN-γ [45]. This may be due to an increased T-regulatory cell response [46].…”

Section: Tlr9-based Adjuvantsmentioning

confidence: 96%

Novel Approaches of Immunotherapy

Stokes

Casale

2013

Curr Treat Options Allergy

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Opinion statementAllergic diseases affect millions of adults and children in the United States. Allergen immunotherapy has been a treatment option for diseases such as allergic rhinitis, allergic asthma, and venom allergy for the last 100 years. In the last 25 years, alternative approaches to traditional subcutaneous immunotherapy have been developed. The purpose of these new therapies is two-fold: to improve safety and to improve the efficacy of allergen immunotherapy. Aluminum hydroxide has been used as an adjuvant to standard immunotherapy, but due to concerns about side effects, its use has been decreasing. The modification of allergens into allergoids has been an effective therapy in Europe, but at this time no preparations are available for use in the United States. Toll-like receptors have demonstrated mixed results with early trials in the United States, showing promise with the use of a TLR4 agonist, while a TLR9 agonist had disappointing results. Early studies with the use of virus-like particles with and without allergens have shown additional promise, and further trials are currently underway. These novel approaches may improve the immunologic response and often the clinical outcomes for the management of allergic diseases.

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Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA

Cited by 191 publications

References 34 publications

Protective CD8 T Cell Immunity Triggered by CpG-Protein Conjugates Competes with the Efficacy of Live Vaccines

Protective CD8 T Cell Immunity Triggered by CpG-Protein Conjugates Competes with the Efficacy of Live Vaccines

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Novel Approaches of Immunotherapy

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